Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing
Reexamination Certificate
2000-06-13
2004-09-14
Wehbe, Anne M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
C435S325000, C435S347000, C435S373000, C435S382000, C435S383000
Reexamination Certificate
active
06790441
ABSTRACT:
BACKGROUND OF THE INVENTION
1. TECHNICAL FIELD
The present inventions relates to methods of transplanting cells. More specifically, the present invention relates to methods of transplanting cells to create a localized immunosuppressive effect in the tissue receiving the transplanted cells.
2. BACKGROUND ART
The central nervous system (CNS) has poor regenerative capacity which is exemplified in a number of neurodegenerative disorders. An example of such a disorder is Parkinson's disease. The prefened pharmacotherapy for Parkinson's disease is the. administration of L-dopa which slows the progression of this disease in some humans. However, the neuropathological damage and the consequent behavioral deficits is not reversed by this treatment protocol.
Laboratory and clinical studies have shown that the transplantation of cells into the CNS is a potentially significant alternative therapeutic modality for neurodegenetative disorders such as Parkinson's disease (Wictorin et al., 1990; Lindvall et al, 1990; Sanberg et al., 1994; Bjorlund and Stenevi, 1985; Freeman et al, 1994). In some cases, transplanted neural tissue can survive and form connections with the CNS of the recipient (i.e. the host). When successfully accepted by the host, the transplanted tissue (i.e. the graft) has been shown to ameliorate the behavioral deficits associated with the disorder (Wictorin et al, 1990). The obligatory step for the success of this kind of treatment is the prevention of graft rejection (i.e. graft acceptance).
Currently, fetal neural tissue is the primary graft source for neural transplantation (Lindvall et al., 1990; Bjorklund, 1992; Isacson et al., 1986; Sanberg et, al 1994). Other viabie graft sources inclcude adrenal chromaffin cells and various cell types that secrete nerve growth factors and trophic factors. The field of neural tissue transplantation as a productive treatment protocol for neurodegenerative disorders has received much attention resulting in its progression to clinical trials. Preliminary results and clinical observations are promising although the graft rejection phenomenon remains problematic.
Transplantation is also a valuable therapy for other diseases, such as insulin dependent diabetes mellitus. Insulin dependent diabetes mellitus is a major health problem. Current forms of therapy are not efficient and do not necessarily lead to a prevention of diabetic complications such as renal failure or blindness. A desirable treatment alternative is to provide the diabetic with an endogenous source of insulin, transplanting either the whole pancreas or the endocrine component of the pancreas (i.e. islets of Langerhans) into the diabetic recipient. Although, whole pancreas transplantation is successfully achieved with at least 60% of the grafts still functioning after transplantation for one year, a major weakness of this approach is the need for continuous immunosuppfessicn with powerful and toxic immunosuppressant drugs.
The transplantation of the isolated islets containing the insulin secreting &bgr;-cells has received much attention in both animal models of diabetes (1-7) and in humans (8-16). However, islet transplantation to a variety of organ sites has met with little success as a viable treatment for diabetes. For example, islet transplantation of major histocompatibility complex (MHC) In the BB/W rat with spontaneous diabetes mellitus of autoimmune etiology results in destroyed islets within a few days by a recurrence of the autoimmune disease (17). Likewise, destruction of grafted cells in the diabeiic BB/W rat occurs in grafted islets of MHC-incompatibie donors (18, 19). In the course of finding a suitable organ or tissue site for islet transplantation, it was discovered that the relocated abdominal testis, in particular, provides an extraordinary safe environment for extended survival of islet grafts and some relief of the diabetic complications (20-22).
The testis has long been considered to be an immunologically privileged site (23-26) although the precise mechanism(s) by which it protects (suppresses) graft rejection has not been clearly defined. Isolated islets of MHC-compatible donors have been shown to survive for extended periods of time in the non-imminosuppressed BB/W rat if implanted in the rat's testis which is then placed into the host's abdominal cavity (20-22,27). Although the maintenance of functional islets allografts is significant, a more difficult task and far more potentially significant accomplishment, in terms of clinical applicability, is the induction of normoglycemia in diabetic animals by the implantation of cross-species islet xenografts.
Selawry and co-workers demonstrated the feasibility of such a procedure by successfully implanting incubated hamster islets into the BB/W rat abdominal testes (22,27,28). As a result of the abdominal testis/islet implant, the diabetic animals in these studies became normoglycemic. Long-term survival of the islet xenografts did not require prolonged immunosuppression to prevent rejection and to maintain normal sugar levels. In all cases implant viability required the protective milieu of the abdominal testis. It now appears that the donor origin of these isolated islets does not seem to influence their long-term survival. Islet cells grafted against major histocompatibility barriers (21), islet xenografts (27) and islets of MHC-compatible donors grafted into the testes of the diabetic BB/W rats functioned indefinitely in the recipient rendering the once diabetic animal normoglycemic.
The major weakness of this type of islet transplantation protocol is associated with the use of such an unconventional organ site. One major concern is the possibility of malignant transformation of germ cells at the higher core body temperature (29). More importantly, it would not be possible to use this transplantation protocol for the treatment of female diabetics.
Histological examination of grafted abdominal testes has shown that the islet implants are always found within the interstitial compartment of the gonad, which consists of the endocrine cells of Leydig, macrophages, blood vessels, testicular interstitial fluid and extracellular macromolecules (31). Any of the secretory products of these cells are potentially capable of inhibiting the immune response. For instance, Born and Wekerie (32, 33) showed that active suppression of immune responses occurred by Leydig cells in vitro. These investigators speculated that the Leydig cells might prevent lymphocyte proliferative responses by creating an “immunologically neutral zone” around the seminiferous tubules and thus decreasing the danger of T-cell infiltration in to the intratubular spaces. It was shown by Williams (34) that leukemic cells accumulate in the interstitial compartment where they are apparently protected against destruction by the host's immune defenses.
The “zone of protection” theory of Born and Wekerle (32) is attractive but it is not likely that this major component of the testicular interstitium, i.e. Leydig cells, is responsible for the synthesis of some protective (immunosuppressant) factor. Treatment of rats with ethane dimethanesulphonate (EDS), which selectively destroys the Leydig cell completely, including steroidogenesis and all other functions, had no adverse effects on the survival of intratesticular islet allografts (30). It is not probable that germ cells were involvedeither, since these cells are readily depleted in the abdominal testis. By eliminatin of these coils, Cameron and Sewiary concluded that the Sertoli cell was the most probable testicular cell type providing the testis with its unique immunologically privileged environment and that this cell was most likely responsible for the unexplained absence of islet rejection in abdominal testes (30). Based on these findings, Selawry and Cameron (35) attempted to create a similar immunologically privileged site outside of the testis utilizing Serioli cells as an immunosuppressant agent. To this end, isolated Sertoli cells were transplanted with isolated i
Cameron Don F.
Hushen Joelle J.
Sanberg Paul R.
Saporta Samuel
Li Q. Janice
Saliwanchik Lloyd & Saliwanchik
University of South Florida
Wehbe Anne M.
LandOfFree
Sertoli cells as biochambers does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Sertoli cells as biochambers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Sertoli cells as biochambers will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3218555